Glucagon, as with most therapeutic peptides and proteins, is thermally unstable. In aqueous solution, glucagon both degrades and begins to form aggregates within hours at room temperature. As a result, glucagon must be stored as a lyophilized powder that requires storage under controlled conditions of temperature and humidity. Lyophilized glucagon for injection is a 29 amino acid synthetic peptide hormone commercially available in a kit including diluent for resuspension, and is marketed as GlucaGen® HypoKit by Novo Nordisk and by Eli Lilly. The diluent for 1 mg of lyophilized glucagon contains 12 mg/mL glycerin, water for injection, and hydrochloric acid to adjust to pH ˜2.
The lyophilized glucagon must be reconstituted with a diluent prior to its use, such as emergency cases of diabetic hypoglycemia. This delays treatment. Also, since the formulation must be stored at 20-25° C., the patient cannot carry it with them. This still further delays treatment.
The thermal, chemical, and physical instability of lyophilized and aqueous glucagon also prohibit current formulations from inclusion in pump-based therapies, where the pump is kept on the patient (i.e., temperature >25° C.), which could otherwise offer enhanced treatment for diabetic patients.
There is a longstanding, unmet clinical need for a pre-constituted, thermally, chemically, and physically stable glucagon formulation.
Therefore, it is an object of the invention to provide pre-constituted, thermally, chemically, and physically stable glucagon formulations and methods of making and using thereof.